This project is designed to identify the role of GRHL2 in oral cancer, and the mechanism by which dysregulation of GRHL2 leads to oral carcinogenesis. GRHL2 is a transcription factor shown to regulate keratinocyte proliferation, and is expressed in epithelial cancers such as breast cancer. Our laboratory has found that GRHL2 is highly expressed in oral squamous cell carcinoma (OSCC) cell lines and that it plays an important role in keratinocyte self-renewal by binding to and epigenetically silencing epithelial differentiation complex (EDC) gene expression. Thus, this proposal aims to 1) investigate the role of abnormal GRHL2 expression on oral cancer formation and metastasis, and 2) identify the epigenetic mechanisms by which GRHL2 promotes keratinocyte proliferation. This research strategy is an integral component of a research- training plan designed to develop the trainee's expertise in oral carcinogenesis, keratinocyte biology and epigenetics. This plan will utilize GRHL2 knockout mice to investigate changes in EDC gene expression, as well as potential for oral cancer tumor growth, metastasis, and development of cancer stemness. Further, chromatin immunoprecipitation followed by high throughput sequencing (ChIP-Seq) will be used to examine changes in epigenetic marks on binding sites of GRHL2 between replicating and differentiated keratinocytes. Lastly, deletion mutants of GRHL2 will be constructed to examine direct binding to epigenetic regulatory proteins. This training will prepare the trainee for an academic career as an independent researcher studying cancer pathobiology and epigenetics.